This invention relates to a series of fused polycyclic 2-aminopyrimidines, to processes for their preparation, to pharmaceutical compositions containing them, and to their use in medicine.
Protein kinases participate in the signalling events which control the activation, growth and differentiation of cells in response to extracellular mediators and to changes in the environment. In general, these kinases fall into two groups; those which preferentially phosphorylate serine and/or threonine residues and those which preferentially phosphorylate tyrosine residues [Hanks, S K, Hunter T, FASEB. J. 9, 576-596 (1995)]. The serine/threonine kinases include for example, protein kinase C isoforms [Newton A C, J. Biol. Chem. 270, 28495-28498 (1995)] and a group of cyclin-dependent kinases such as cdc2 [Pines J, Trends in Biochemical Sciences 18, 195-197 (1995)]. The tyrosine kinases include membrane-spanning growth factor receptors such as the epidermal growth factor receptor [Iwashita S and Kobayashi M. Cellular Signalling 4, 123-132 (1992)], and cytosolic non-receptor kinases such as p56lck p59fyn ZAP-70 and csk kinases [Chan C et al Ann. Rev. Immunol. 12, 555-592 (1994)].
Inappropriately high protein kinase activity has been implicated in many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, for example by failure of the proper control mechanisms for the kinase, related for example to mutation, overexpression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signal upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect.
We have now found a series of 2-aminopyrimidine derivatives which are potent and selective inhibitors of the protein tyrosine kinases p56lck and p59fyn. The compounds are of use in the prophylaxis and treatment of immune diseases, hyperproliferative disorders and other diseases in which inappropriate p56lck and/or p59fyn activity is believed to have a role.
Thus according to one aspect of the invention, we provide a compound of formula (1): 
wherein
Ar is an optionally substituted aromatic or heteroaromatic group;
X is a carbon or nitrogen atom;
Y is a carbon or nitrogen atom;
Z is a linker group;
A together with X and Y forms an optionally substituted monocyclic or bicyclic aromatic or heteroaromatic group;
and the salts, solvates, hydrates and N-oxides thereof.
Aromatic groups represented by the group Ar in compounds of formula (1) include for example mono- or bicyclic C6-12 optionally substituted aromatic groups, for example optionally substituted phenyl, 1- or 2-naphthyl, or indenyl groups.
Heteroaromatic groups represented by Ar include for example C1-9 optionally substituted heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups represented by Ar include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl.
Optional substituents present on the aromatic or heteroaromatic groups represented by Ar include one, two, three or more groups, each represented by the group R1. The substituent R1 may be selected from an atom or group R2 or -Alk(R2)m, where R2 is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH) substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR3 (where R3 is an -Alk(R2)m, aryl or heteroaryl group), xe2x80x94CSR3, xe2x80x94SO3H, xe2x80x94SO2R3, xe2x80x94SO2NH2, xe2x80x94SO2NHR3, SO2N(R3)2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR3, xe2x80x94CSNHR3, xe2x80x94CON(R3)2, xe2x80x94CSN(R3)2, xe2x80x94NHSO2H, xe2x80x94NHSO2R3, xe2x80x94N(SO2R3)2, xe2x80x94NHSO2NH2, xe2x80x94NHSO2NHR3, xe2x80x94NHSO2N(R3)2, xe2x80x94NHCOR3, xe2x80x94NHCSR3, xe2x80x94NHC(O)OR3, aryl or heteroaryl group; Alk is a straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94S(O)n (where n is an integer 1 or 2) or xe2x80x94N(R4)xe2x80x94 groups (where R4 is a hydrogen atom or C1-6alkyl, e.g. methyl or ethyl group); and m is zero or an integer 1, 2 or 3.
When in the group -Alk(R2)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R2 may be present on any suitable carbon atom in -Alk. Where more than one R2 substituent is present these may be the same or different and may be present on the same or different atom in -Alk. Clearly, when m is zero and no substituent R2 is present the alkylene, alkenylene or alkynylene chain represented by Alk becomes an alkyl, alkenyl or alkynyl group.
When R2 is a substituted amino group it may be for example a group xe2x80x94NHR3[where R3 is as defined above] or a group xe2x80x94N[R3]2 wherein each R3 group is the same or different.
When R2 is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R2 is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR3 or a xe2x80x94SR3 or xe2x80x94SC(NH2+)NH2 group respectively.
Esterified carboxyl groups represented by the group R2 include groups of formula xe2x80x94CO2Alk1 wherein Alk1 is a straight or branched, optionally substituted C1-8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C6-12arylC1-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12aryloxyC1-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyl-oxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk1 group include R2 substituents described above.
When Alk is present in or as a substituent R1 it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R4)xe2x80x94 groups.
Aryl or heteroaryl groups represented by the groups R2 or R3 include mono- or bicyclic optionally substituted C6-12 aromatic or C1-9 heteroaromatic groups as described above for the group Ar. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
Particularly useful atoms or groups represented by R1 include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl or ethyl, C1-6alkylamino, e.g. methylamino or ethylamino, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, C1-6alkylenethiol e.g. methylenethiol or ethylenethiol, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. hydroxyethoxy, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC1-6alkyl, e.g. trifluoromethyl, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, isopropylaminoethoxy, or dimethylaminopropoxy, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, 1,1,3-trioxobenzo[d]thiazolidino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl (HC(O)xe2x80x94), carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk1 (where Alk1 is as defined above), C1-6alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(NH2+)NH2, sulfo (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methyl-sulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaninosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminbC1-6alkylamino-carbonyl, e.g. diethylaminoethylaminocarbonyl, xe2x80x94CONHC(xe2x95x90NH)NH2 sulphonylamino (xe2x80x94NHSO2H), C1-6alkylsulphonyl-amino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, e.g. 2-, 3- or 4-substituted phenylsulphonylamino such as 2-nitrophenylsulphonylamino, amino-sulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamnino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, phenylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, aminoC1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, benzyloxycarbonylamino or benzyloxycarbonylaminoC1-6alkyl e.g. benzyloxycarbonylaminoethyl groups.
Where desired, two R1 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R1 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the R1 substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group.
Linker groups represented by the group Z in compounds of formula (1) include groups of formula -(Alk2)r(L1)s(L2)t(Alk3)uxe2x80x94 where Alk2 and Alk3 which may be the same or different is each an optionally substituted straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, L1 and L2 is each an xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atom or a xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94C(NR4)xe2x80x94, xe2x80x94CON(R4)xe2x80x94, xe2x80x94CSN(R4)xe2x80x94, xe2x80x94N(R4)SOxe2x80x94, xe2x80x94N(R4)SO2xe2x80x94, xe2x80x94N(R4)SO2N(R4)xe2x80x94, xe2x80x94N(R4)SON(R4), or xe2x80x94N(R4)CON(R4) group and r, s, t and u which may the the same or different is each zero or the integer 1, provided that when one of r, s, t or u is zero at least one of the remainder is the integer 1. It will be appreciated that when two or more L atoms or groups are present, such atoms or groups are adjacent to one another and, for example form a chain xe2x80x94N(R4)C(NR4)xe2x80x94N(R4) or xe2x80x94OCON(R4)xe2x80x94.
The heteroatoms which may interrupt the Alk2 or Alk3 chains include for example xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms. Particular heteroatom-containing groups which may interrupt Alk2 or Alk3 include oxygen-, sulphur- or nitrogen-containing groups such as xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2, xe2x80x94N(R4),
Optional substituents which may be present on Alk2 or Alk3 chains include one, two or more halogen atoms such as chlorine, fluorine, bromine or iodine atoms and C1-3alkyl groups such as methyl or ethyl groups.
Particular examples of linker groups Z include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, or xe2x80x94(CH2)3xe2x80x94 chains, especially xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, xe2x80x94CH2C(CH3)2xe2x80x94 or xe2x80x94C(CH3)2CH2xe2x80x94 chains, xe2x80x94CH2Sxe2x80x94, xe2x80x94CH(CH3)Sxe2x80x94, xe2x80x94C(CH3)2Sxe2x80x94, xe2x80x94SCH2, xe2x80x94CH2Oxe2x80x94, xe2x80x94OCH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94 chains.
When A together with X and Y in compounds of formula (1) form an optionally substituted monocyclic or bicyclic aromatic group [i.e. when X and Y is each a carbon atom] the aromatic group may be an optionally substituted monocyclic or bicyclic C6-12aromatic group such as an optionally substituted phenyl, 1- or 2- naphthyl or indenyl group.
In compounds of formula (1) when A together with X and Y from an optionally substituted monocyclic or bicyclic heteroaromatic group [i.e. X and Y is each a -carbon or nitrogen atom], the heteroaromatic group may be an optionally substituted monocyclic or bicyclic C1-9heteroaromatic group containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example nine- to thirteen-membered heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups represented by A, X and Y together include optionally substituted pyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethyl-imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl.
Optional substitutents which may be present on aromatic or heteroaromatic groups represented by A, X and Y together include one, two, three or more substituents selected from fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl or ethyl, C1-6alkylamino, e.g. methylamino or ethylamino, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, C1-6alkylenethiol e.g. methylenethiol or ethylenethiol, C1-6alkoxy, e.g. methoxy or ethoxy, haloC1-6alkyl, e.g. trifluoromethyl, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy or dimethylaminopropoxy, nitro, cyano, hydroxyl (xe2x80x94OH), formyl (HC(O)xe2x80x94), carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk1 (where Alk1 is as defined above), C1-6alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(NH2+)NH2, sulfo (xe2x80x94SO3H), C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C,dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6 dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, sulphonylamino (xe2x80x94NHSO2H), C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, e.g. 2-, 3- or 4-substituted phenylsulphonylamino such as 2-nitrophenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, phenylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, aminocarbonylamino (xe2x80x94NHCONH2), C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminoarbonylamino or diethylaminocarbonylamino, C1-6alkoxy carbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino groups.
In general the substituent(s) may be present on any available ring atom in the aromatic or heteroaromatic group. Where desired, two of these substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as a methylenedioxy or ethylenedioxy group.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
It will be appreciated that where compounds of formula (1) exist as geometrical isomers and/or enantiomers or diasteromers then the invention extends to all such isomers of the compounds of formula (1), and to mixtures thereof, including racemates.
One particularly useful group of compounds according to the invention is that wherein Ar is an optionally substituted aromatic group. Particularly useful compounds of this type are those wherein Ar is an optionally substituted phenyl group. In compounds of this type Ar may be in particular a phenyl group or a phenyl group substituted by one, two, three or more R1 groups as defined herein. Especially useful Ar groups include phenyl or monosubstituted phenyl groups where the substituent is a R1 group as defined herein and is particularly an alkylaminoethoxy or dialkylaminoethoxy group especially a methylaminoethoxy or dimethylaminoethoxy group.
In another preference, A together with X and Y is preferably an optionally substituted phenyl group, the optional substituents being those previously generally and particularly described above. In one preference, A together with X and Y is a phenyl or monosubstituted phenyl group. Particularly useful substituents include methoxy groups.
Z in compounds of formula (1) is preferably an optionally substituted xe2x80x94(CH2)2xe2x80x94 group. Particular examples of groups of this type include xe2x80x94(CH2)2xe2x80x94, xe2x80x94CH2CH(CH3)xe2x80x94 or xe2x80x94CH2C(CH3)2xe2x80x94 groups.
Particularly useful compounds according to the invention include those described in the Examples hereinafter and especially include:
N-[4-(2-Dimethylaminoethoxy)phenyl]-9-methoxy-benzo[h]-5,6-dihydroquinazoline-2-amine;
6,6-Dimethyl-N-(4-[2-dimethylaminoethoxy]phenyl)-benzo[h]-5,6-dihydroquinazoline-2-amine;
6,6-Dimethyl-N-(4-[2-dimethylaminoethoxy]phenyl)-9-methoxy-benzo[h]-5,6-dihydroquinazoline-2-amine;
N-[4-(2-Dimethylaminoethoxy)phenyl]-9-methoxy-6-methyl-benzo[h]-5,6-dihydroquinazoline-2-amine;
and the salts, solvates, hydrates and N-oxides thereof.
Compounds according to the invention are potent and selective inhibitors of the protein tyrosine kinases p56lck and p59fyn. In particular, compounds of the invention inhibit these enzymes at concentrations at which they have little or no useful inhibitory action on other protein kinases, in particular ZAP-70, protein kinase C and Csk kinases. The ability of the compounds to act in this way may be simply determined by the tests described in the Examples hereinafter.
The compounds according to the invention are thus of particular use in the prophylaxis and treatment of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus, in transplant rejection, in graft v host disease, in hyperproliferative disorders such as tumours and psoriasis, and in diseases such as asthma and inflammatory bowel disease.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Altematively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular. injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg e:g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols Ar, X, Y, Z and A when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.
Thus according to a further aspect of the invention, a compound of formula (1) may be prepared by reaction of a guanidine of formula (2): 
or a salt thereof
with an enaminone of formula (3): 
where R5 and R6, which may be the same or different is each a C1-6 alkyl group.
The reaction may be performed in a solvent, for example a protic solvent such as an alcohol, e.g. ethanol, methoxyethanol, propanol or isopropanol, optionally in the presence of a base e.g. an alkali metal base, such as sodium hydroxide or potassium carbonate, at an elevated temperature, e.g. the reflux temperature.
Salts of the compounds of formula (2) include acid salts such as inorganic acid salts e.g. hydrochlorides, nitrates or carbonates.
Intermediate guanidines of formula (2) may be prepared by reaction of the corresponding amine ArNH2 with cyanamide at an elevated temperature. The reaction may be performed in a solvent such as ethanol at an elevated temperature, e.g. up to the reflux temperature. Where it is desired to obtain a salt of a guanidine of formula (2), the reaction may be performed in the presence of a concentrated acid, e.g. hydrochloric or nitric acid.
The amines ArNH2 are either known compounds or may be obtained by conventional procedures, for example by hydrogenation of the corresponding nitro derivatives using for example hydrogen in the presence of a metal catalyst in a suitable solvent, for example as more particularly described in the interconversion reactions discussed below. The nitrobenzenes for this particular reaction are either known compounds or may be prepared using similar methods to those used for the preparation of the known compounds.
Intermediate enaminones of formula (3) are either known compounds or may be prepared by reaction of a ketone of formula (4): 
with an acetal (R5)(R6)NCH(OCH3)2 at an elevated temperature. The starting materials for this reaction are either known compounds of may be prepared by methods analogous to those used for the preparation of the known compounds using simple chemical manipulations, for example as described in the Examples hereinafter.
In another process according to the invention, compounds of formula (1) may be prepared by reaction of an amine ArNH2 with a compound of formula (5): 
where Hal is a halogen atom such as a chlorine atom.
The reaction may be performed at an elevated temperature, for example the reflux temperature, where necessary in the presence of a solvent, for example a ketone such as acetone, an alcohol such as ethanol or 2-ethoxyethanol or an aromatic hydrocarbon such as toluene, optionally in the presence of a base, for example an organic amine such as triethylamine or pyridine, or an acid, for example an inorganic acid such as hydrochloric acid.
The intermediates of formula (5) may be prepared by heating the corresponding alcohols of formula (6): 
with a phosphorous oxyhalide in a solvent such as dimethylformamide at an elevated temperature such as the reflux temperature.
Alcohols of formula (6) may be obtained from the corresponding amines of formula (7): 
by reaction with a nitrite, e.g. sodium nitrite in an aqueous acidic solution followed by treatment with a base, for example an inorganic base such as sodium hydroxide or an ammonium base such as aqueous ammonia.
Amines of formula (7) may be prepared by reaction of an enaminone of formula (3) with guanidine or a salt thereof using the reaction conditions described above for the preparation of compounds of formula (1) from compounds of formula (3).
Compounds of formula (1) may also be prepared by interconversion of other compounds of formula (1) and it is to be understood that the invention extends to such interconversion processes. Thus, for example, standard substitution approaches employing for example alkylation, arylation, acylation, thioacylation, sulphonylation, formylation or coupling reactions may be used to add new substitutents to and/or extend existing substituents in compounds of formula (1). Alternatively existing substituents in compounds of formula (1) may be modified by for example oxidation, reduction or cleavage reactions to yield other compounds of formula (1).
The following describes in general terms a number of approaches which can be employed to modify existing Ar and aromatic or heteroaromatic groups represented by groups X, Y and A together in compounds of formula (1). It will be appreciated that each of these reactions will only be possible where one or more appropriate functional groups exist in the compound of formula (1).
Thus, for example alkylation or arylation of a compound of formula (1), for example to introduce a group Alk(R5)m or R5 where R5 is an aryl group may be achieved by reaction of the compound with a reagent (R5)mAlkL2 or R5L2, where L2 is a leaving group.
Leaving groups represented by L2 include halogen atoms such as iodine, chlorine or bromine atoms or sulphonyloxy groups such as alkyl- or arylsulphonyloxy groups, e.g. methylsulphonyloxy or p-toluenesulphonyloxy.
The alkylation or arylation reaction may be carried out in the presence of a base, e.g. an inorganic base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran, at around 0xc2x0 C. to around 120xc2x0 C.
In another general example of an interconversion process, a compound of formula (1) may be acylated or thioacylated, for example to introduce a group xe2x80x94C(O)R3 or xe2x80x94C(S)R3. The reaction may be performed for example with an acyl or thioacyl halide or anhydride in the presence of a base, such as a tertiary amine e.g. triethylamine in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at for example ambient temperature, or by reaction with a thioester in an inert solvent such as tetrahydrofuran at a low temperature such as around 0xc2x0 C.
Compounds of formula (1) may be prepared in another general iriterconversion reaction by sulphonylation, for example by reaction of the compound with a reagent R2S(O)L2 or R2SO2L2 where L2 is a leaving group as described above in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature. The reaction may in particular be performed with compounds of formula (1) in which Ar and/or X, Y and A together possesses a primary or secondary amino group.
In further examples of interconversion reactions according to the invention compounds of formula (1) may be prepared from other compounds of formula (1) by modification of existing functional groups in the latter.
Thus in one example, ester groups xe2x80x94CO2Alk1 in compounds of formula (1) may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis depending on the nature of the group Alk1. Acid- or base-catalysed hydrolysis. may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a second example, xe2x80x94OR3 [where R3 represents an alkyl group such as methyl group] groups in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
Alcohol [xe2x80x94OH] groups may also be obtained by hydrogenation of a corresponding xe2x80x94OCH2Ar group using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, xe2x80x94OH groups may be generated from the corresponding ester [xe2x80x94CO2Alk1] or aldehyde [xe2x80x94CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol xe2x80x94OH groups in compounds of formula (1) may be converted to a corresponding xe2x80x94OR3 group by coupling with a reagent R3OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NH2] groups in compounds of formula (1) may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with sulphamide in, the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In another example of an interconversion reaction, amine (xe2x80x94NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, Where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
In a further example, amide [xe2x80x94CONHR3] groups in compounds of formula (1) may be obtained by coupling a corresponding acid [xe2x80x94CO2H] or an active derivative thereof, e.g. an acid anhydride, ester, imide or halide, with an amine R3NH2. The coupling reaction may be performed using standard conditions for reactions of this type. Thus for example the reaction may be carried out in a solvent, for example an inert organic solvent such as an amide, e.g. a substituted amide such as dimethylformamide, at a low temperature, e.g. xe2x88x9230xc2x0 C. to ambient temperature, optionally in the presence of a base, e.g. an organic base such as a cyclic amine, e.g. N-methylmorpholine, and where necessary in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
Aromatic halogen substituents in compounds of the invention may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around xe2x88x9278xc2x0 C., in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyidisulphide as the electrophile.
In another example, sulphur atoms in compounds of the invention, for example when present in the linker group Z, may be oxidised to the corresponding sulphoxide using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
In a still further example, compounds of the invention may be prepared by aromatisation of a corresponding hydroaromatic compound. Thus, for example, a compound of formula (1) wherein the linker group Z is a xe2x80x94CH2xe2x80x94CH2xe2x80x94 chain may be treated with a hydrogen acceptor, for example a quinone such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in a solvent such as an ether, e.g. a cyclic ether such as dioxane, at an elevated temperature, e.g. the reflux temperature, to yield a corresponding compound in which Z is a xe2x80x94CHxe2x95x90CHxe2x80x94 chain.
Nxe2x80x2-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or altematively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.